Ventral tegmental area (VTA) dopamine neurons play important roles in adaptive and pathological brain functions related to reward and motivation. It is unknown, however, if subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures and whether inputs to the VTA differentially modulate such circuits. Here we show that because of differences in synaptic connectivity activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to nucleus accumbens lateral shell while lateral habenula neurons synapse primarily on dopamine neurons projecting to medial prefrontal cortex as well as on GABAergic neurons in the VTA tail. These results establish that distinct VTA circuits generate reward and aversion and thereby provide a novel framework for understanding the circuit basis of adaptive and pathological motivated behaviors.

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Aging impairs tissue repair. This is pronounced in skeletal muscle, whose regeneration by muscle stem cells (MuSCs) is robust in young adult animals but inefficient in older organisms. Despite this functional decline, old MuSCs are amenable to rejuvenation through strategies that improve the systemic milieu, such as heterochronic parabiosis. One such strategy, exercise, has long been appreciated for its benefits on healthspan, but its effects on aged stem cell function in the context of tissue regeneration are incompletely understood. Here we show that exercise in the form of voluntary wheel running accelerates muscle repair in old animals and improves old MuSC Reprints and permissions information is available at http://www.nature.com/reprints.

Physical exercise seems universally beneficial to human and animal health, slowing cognitive aging and neurodegeneration. Cognitive benefits are tied to increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms mediating these effects. We discovered "runner" plasma, collected from voluntarily running mice, infused into sedentary mice recapitulates the cellular and functional benefits of exercise on the brain. Importantly, runner plasma reduces baseline neuroinflammatory gene expression and prominently suppresses experimentally induced brain inflammation. Plasma proteomic analysis shows a striking increase in complement cascade inhibitors including clusterin, which is necessary for the anti-inflammatory effects of runner plasma. Cognitively impaired patients participating in structured exercise for 6 months showed higher plasma clusterin levels, which correlated positively with improvements in endurance and aerobic capacity. These findings demonstrate the existence of anti-inflammatory "exercise factors" that are transferrable, benefit the brain, and are present in humans engaging in exercise.Physical activity evokes profound physiological responses in multiple tissues in species from fish, to birds, rats, mice and humans 1-6 . It is widely accepted and promoted as a method of improving human health, including brain health 7-9 . Exercise interventions in people of various ages with or without neurodegenerative diseases, or brain damage, have been shown to improve cognitive function 9,10,11,12 . Neuroinflammation is a common feature of these conditions and potential mediator of the cognitive impairment associated with them [13][14][15][16] . Studies in mouse models of aging and neurodegenerative diseases, such as AD and Parkinson disease have linked long-term voluntary wheel running with improved learning and memory, and decreased neuroinflammation 17-20 . However, how exercise exerts these beneficial effects on the brain is poorly understood. It is possible that the physical exertion of muscle or lung during exercise may result in the secretion of factors from these or other tissues which subsequently signal to the brain to reduce neuroinflammation. Indeed, physical exercise increases levels of dozens of proteins in plasma, many of which are likely released from muscle tissue and thus named myokines 2,21 . Some of these myokines, such as insulin-like growth factor-1 (IGF-1) 22 , vascular endothelial growth factor (VEGF) 23 and platelet factor 4 (PF4) 24 increase following exercise and have been shown to increase hippocampal neurogenesis (Extended Table 1). However, it is unknown whether exercise conditioned plasma contains the factors benefitting the brain, whether these factors are directly transferrable through plasma, how such factors impact the brain, and what the key factors are. Runner plasma infusions induce neuroplasticity, improve learning and memory and regulate transcription of genes associated with the acute inflammatory response in the h...

Chronic consumption of specific plant species from the genera Oxytropis, Astragalus, lpomeoa, and Swainsonia, commonly known as locoweeds, is well known to induce locoism in grazing animals. Locoism in cattle is characterized by sensory deficits, ataxia, behavior changes, loss of condition, and failure to grow. The toxic principle swainsonine is rapidly absorbed and distributed through the bloodstream to multiple organs where it inhibits cellular lysosomal alphamannosidase and Golgi mannosidase II, leading to lysosomal dysfunction and disruption of glycoprotein processing. Excessive mannose-rich oligosaccharide accumulations cause cytoplasmic vacuolation and cellular dysfunction. In addition to neurologic disease, chronic consumption of locoweeds is known to induce abortion and embryonic death in neurologically affected dams. We describe multiple cases of bovine abortion associated with chronic locoweed ingestion in non-clinical dams from a herd in southeastern Colorado. Neurons from the cerebral cortex, brainstem, cerebellum, and renal tubular epithelial cells displayed the characteristic cytoplasmic vacuolation observed in adult cases of locoism in the aborted animals. Although chronic ingestion of locoweed is widely known to cause early gestation embryonic death, late-term hydrops amnii, and fetal fluid accumulation, locoweed-induced abortion should be considered as a differential diagnosis for cases ofnon-infectious abortion in grazing cattle, even in the absence of maternal clinical signs. These findings indicate that the bovine fetus may be more sensitive to the abortive effects of swainsonine than previously thought.